Immune-Checkpoint Inhibitors: Cancer Breakthrough?

April 02, 2014|By ARTHUR ALLEN, Special To The Washington Post

In the summer of 2012, a year after his wife had died of lung cancer, Michael Harris scraped open an old mole on his back and it would not stop bleeding. The doctors said he had stage 4 melanoma, with a virtually inoperable tumor, and that patients in his condition typically lived about eight months. By last June, the cancer had spread to his liver and lungs.

At that point Harris joined a clinical trial at Georgetown University in Washington, one of scores that have sprung up around the country to test a new class of cancer drugs called immune-checkpoint inhibitors. Two weeks after his first infusion, Harris' primary tumor was fading, along with the black cancerous beads around it. A month later, his liver and lungs were clean.

"This stuff was like vanishing cream," says Harris' daughter, Rhonda Farrell. Today, Harris, a sun-leathered 66-year-old Vietnam veteran from Waldorf, Md., is back at work. And though his doctors won't declare him cured, he says, "I feel like a normal person."

Because it can be so inexorable and deadly, cancer tends to inspire hopes of miracle cures. Because of all the failed miracle cures, cancer doctors are a cautious lot. This makes it all the more astounding to hear cautious clinicians and scientists describe the treatments Harris and thousands of others are receiving.

"It's a breakthrough," says oncologist Michael Atkins, who recruited Harris to the trial at Georgetown's Lombardi Cancer Center. "This is real," adds Louis Weiner, the physician who leads the center. "We're still in a bit of shock," says Suzanne Topalian, a cancer immunologist at Johns Hopkins University who has been a key player in bringing the substances into clinical trials.

Immune-checkpoint blockade is a form of immunotherapy, meaning it aims to help the patient's own immune system fight cancer. It uses substances called monoclonal antibodies, which are designed by drug companies to target extremely specific molecules on cell surfaces. In this case, the antibodies unblock a reaction that stops the immune system's natural attack on invading cancer cells.

Although a range of new cancer treatments, such as targeted chemotherapy for breast cancer and cell-signaling inhibitors for leukemia, have shown positive effects over the past two decades, the checkpoint inhibitors seem to be providing uniquely long-term benefits. At least seven drug companies are testing the antibodies.

Topalian's husband, Drew Pardoll, also a Hopkins cancer immunologist, predicts that five years from now, half of the 600,000 Americans who receive diagnoses of advanced cancer each year will receive checkpoint inhibitors or other immune-related therapies.

Medical, commercial and patient interest in the new drugs is intense. "Research activity is just going through the roof," Topalian says. While Bristol-Myers Squibb, Merck and other companies rush to get their versions of the therapy approved by the Food and Drug Administration for treatment of melanoma and lung and kidney cancers, the substances also are being tested in smaller trials against cancers of the blood, colon, stomach, breast, bladder, liver, head and neck and brain. "The field is just afire now," says immunologist Gordon Freeman of the Dana-Farber Cancer Institute in Boston.

The checkpoint inhibitors may also have uses in battling some chronic infections. Trials using the antibodies against hepatitis B, HIV and even the blood infections that contributes to 200,000 U.S. deaths each year are underway or in planning stages.

Not everyone, though, is convinced that the checkpoint inhibitors are quite so tide-turning. Stephen A. Rosenberg, who has led immunotherapy research for decades at the National Cancer Institute and has studied the checkpoint inhibitors, is a skeptic.

"Because 1 / 8the antibodies 3 / 8 take advantage of natural immune reactions, they only are likely to work in a small number of cancers," Rosenberg says. "The path to treatment of cancers that . . . kill 90 percent of cancer patients is likely to be through genetic manipulation of the immune system." Rosenberg is the pioneer in such genetic treatments. He has had 40 percent cure rates in some small melanoma trials at NIH.

One way our bodies deal with infections, and with cancer is by activating immune cells, called T-cells, which recognize foreign agents and marshal various parts of the immune system to clear or control them. Certain types of T-cells infiltrate tumors and release chemical signals that tell other parts of the immune system to attack. But one of these signals, a chemical called interferon-gamma, tells tumor cells to produce a molecule that actually blocks the T-cell response.

This inactivation switch probably evolved to keep our immune systems from going haywire overreacting and damaging organs. In dealing with cancer, however, the mechanism is a Catch-22, because it allows the cancer to grow.